Sorafenib ameliorates bleomycin-induced pulmonary fibrosis: potential roles in the inhibition of epithelial–mesenchymal transition and fibroblast activation

Abstract

Idiopathic pulmonary fibrosis (IPF) is a serious progressive and irreversible lung disease with unknown etiology and few treatment options. This disease was once thought to be a chronic inflammatory-driven process, but it is increasingly recognized that the epithelial–mesenchymal transition (EMT) contributes to the cellular origin of fibroblast accumulation in response to injury. During the pathogenesis of pulmonary fibrotic diseases, transforming growth factor-β (TGF-β) signaling is considered a pivotal inducer of EMT and fibroblast activation, and a number of therapeutic interventions that interfere with TGF-β signaling have been developed to reverse established fibrosis. However, efficient and well-tolerated antifibrotic agents are not currently available. Previously, we reported the identification of sorafenib to antagonize TGF-β signaling in mouse hepatocytes in vitro. In this manuscript, we continued to evaluate the antifibrotic effects of sorafenib on bleomycin (BLM)-induced pulmonary fibrosis in mice. We further demonstrated that sorafenib not only profoundly inhibited TGF-β1-induced EMT in alveolar epithelial cells, but also simultaneously reduced the proliferation and collagen synthesis in fibroblasts. Additionally, we presented in vivo evidence that sorafenib inhibited the symptoms of BLM-mediated EMT and fibroblast activation in mice, warranting the therapeutic potential of this drug for patients with IPF.

Total glycosides of Yupingfeng protects against bleomycin-induced pulmonary fibrosis in rats associated with reduced high mobility group box 1 activation and epithelial–mesenchymal transition

“…During the past few years, the pathogenesis researches of PF were concentrated upon transforming growth factorb (TGF-b), a signaling which was considered a pivotal inducer of EMT [4,29]. HMGB1 is another crucial factor which plays a pivotal role in the progress of fibrosis [13].…”

“…Hyaluronic acid (HA) and laminin (LN) have emerged as remarkable ECM components by its viscoelastic properties in regulating cell adhesion and spreading [3]. Recent studies have demonstrated that a key step in PF is epithelial-mesenchymal transition (EMT), a progress fully owing to the differentiated epithelial cell transition to mesenchymal phenotype, and fibroblast activation, which causes an anomalous increase of myofibroblasts, subsequently exhibiting an excessive deposition of ECM, such as fibrillar collagen, proteoglycans and structural glycoproteins [4,5]. EMT is characterized by the increase of mesenchymal markers such as vimentin (Vim) and fibronectin, and the suppression of epithelial markers such as E-cadherin (E-cad), which is a transmembrane protein involved in cell adhesion [6,7].…”

Tanshinone IIA ameliorates bleomycin-induced pulmonary fibrosis and inhibits transforming growth factor-beta-β–dependent epithelial to mesenchymal transition

“…Tanjore et al [7] have demonstrated that EMT of alveolar epithelial cells contributes to fibroblasts in bleomycin (BLM)einduced lung fibrosis. It has been suggested that suppression of abnormal EMT process either with exogenous reagents such as methacycline and sorafenib [8,9] or endogenous regulators such as microRNA-26a and microRNA-21 [10,11] can ameliorate pulmonary fibrogenesis. These previous studies support a concept that EMT signaling is important to lung fibrosis, and inhibition of EMT may represent a useful approach to attenuate pulmonary fibrosis.…”

Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

“…Apart from the genetic approaches, small chemicals targeting TGF-β signaling cascade have strong therapeutic potential in preclinical settings (Nanthakumar et al 2015). Notably, sorafenib has been demonstrated to feature the ability to inhibit the profibrogenic activity of TGF-β signaling and ameliorate BLMmediated pulmonary fibrosis (Chen et al 2013). Sunitinib malate (Sutent™) is an oral multikinase inhibitor that shows antitumor and antiangiogenic activities.…”

“…The antifibrotic property of several tyrosine kinase inhibitors has already been investigated in a number of in vitro studies and animal models (Chen et al 2011(Chen et al , 2013. As sunitinib is an inhibitor of multiple receptor tyrosine kinases, it is not surprising to show an inhibitory effect of sunitinib on tyrosine phosphorylation.…”